Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics.

BACKGROUND: Despite recent advances in immunotherapy, a substantial population of late-stage melanoma patients still fail to achieve sustained clinical benefit. Lack of translational preclinical models continues to be a major challenge in the field of immunotherapy; thus, more optimized translational models could strongly influence clinical trial development. To address this unmet need, we designed a preclinical model reflecting the heterogeneity in melanoma patients' clinical responses that can be used to evaluate novel immunotherapies and synergistic combinatorial treatment strategies. Using our all-autologous humanized melanoma mouse model, we examined the efficacy of a novel engineered interleukin 2 (IL-2)-based cytokine variant immunotherapy. METHODS: To study immune responses and antitumor efficacy for human melanoma tumors, we developed an all-autologous humanized melanoma mouse model using clinically annotated, matched patient tumor cells and peripheral blood mononuclear cells (PBMCs). After inoculating immunodeficient NSG mice with patient tumors and an adoptive cell transfer of autologous PBMCs, mice were treated with anti-PD-1, a novel investigational engineered IL-2-based cytokine (nemvaleukin), or recombinant human IL-2 (rhIL-2). The pharmacodynamic effects and antitumor efficacy of these treatments were then evaluated. We used tumor cells and autologous PBMCs from patients with varying immunotherapy responses to both model the diversity of immunotherapy efficacy observed in the clinical setting and to recapitulate the heterogeneous nature of melanoma. RESULTS: Our model exhibited long-term survival of engrafted human PBMCs without developing graft-versus-host disease. Administration of an anti-PD-1 or nemvaleukin elicited antitumor responses in our model that were patient-specific and were found to parallel clinical responsiveness to checkpoint inhibitors. An evaluation of nemvaleukin-treated mice demonstrated increased tumor-infiltrating CD4+ and CD8+ T cells, preferential expansion of non-regulatory T cell subsets in the spleen, and significant delays in tumor growth compared with vehicle-treated controls or mice treated with rhIL-2. CONCLUSIONS: Our model reproduces differential effects of immunotherapy in melanoma patients, capturing the inherent heterogeneity in clinical responses. Taken together, these data demonstrate our model's translatability for novel immunotherapies in melanoma patients. The data are also supportive for the continued clinical investigation of nemvaleukin as a novel immunotherapeutic for the treatment of melanoma.

Evolution of magnetic surfboards and spin glass behavior in (Fe1-pGap)2TiO5.

The unusual anisotropy of the spin glass (SG) transition in the pseudobrookite system Fe2TiO5has been interpreted as arising from an induced, van der Waals-like, interaction among magnetic clusters. Here we present susceptibility (χ) and specific heat data (C) for Fe2TiO5diluted with non-magnetic Ga, (Fe1-pGap)2TiO5, for disorder parameterp= 0, 0.11, and 0.42, and elastic neutron scattering data forp= 0.20. A uniform suppression ofTgis observed upon increasingp, along with a value ofχTgthat increases asTgdecreases, i.e.dχ(Tg)/dTg<0We also observeCT∝T2in the low temperature limit. The observed behavior places (Fe1-pGap)2TiO5in the category of a strongly geometrically frustrated SG.

Observation of Linear and Nonlinear Light Localization at the Edges of Moiré Arrays.

We observe linear and nonlinear light localization at the edges and in the corners of truncated moiré arrays created by the superposition of periodic mutually twisted at Pythagorean angles square sublattices. Experimentally exciting corner linear modes in the femtosecond-laser written moiré arrays we find drastic differences in their localization properties in comparison with the bulk excitations. We also address the impact of nonlinearity on the corner and bulk modes and experimentally observe the crossover from linear quasilocalized states to the surface solitons emerging at the higher input powers. Our results constitute the first experimental demonstration of localization phenomena induced by truncation of periodic moiré structures in photonic systems.

[A preliminary study on the establishment of a subcutaneous allergen-specific immunotherapy center].

Allergic diseases can notably affect a patient's quality of life. World Health Organization (WHO) has identified these diseases as one of the key areas for research and prevention in the 21st century. Currently, allergen-specific immunotherapy is viewed as a potential treatment approach that could modify the natural progression of allergic diseases, thus being recognized as a crucial tactic in their prevention and treatment. Nonetheless, the broad implementation of allergen-specific immunotherapy in clinical settings continues to confront challenges. One significant issue is the absence of standardized centers for subcutaneous allergen-specific immunotherapy. This article presents several perspectives and recommendations for establishing a standardized subcutaneous allergen-specific immunotherapy center.

[Value of dual-layer spectral detector CT in preoperative prediction of lymph node metastasis of gastric cancer].

Objective: To investigate the value of dual-layer spectral detector CT(SDCT) in preoperative prediction of lymph node (LN) metastasis of gastric cancer. Methods: From January 2019 to January 2021, the clinical and imaging data of 130 gastric cancer patients(93 males and 37 females, aged from 37 to 84 years)confirmed by pathology in the Zhongshan hospital of Xiamen University were retrospectively collected. According to the status of lymph node metastasis, those patients were divided into metastatic LNs group (n=104) and nonmetastatic LNs group (n=26). The maximum diameter of gastric cancer on spectral CT images, CT Values of lesions in 40, 50, 60, 70. KeV monoenergetic image of arterial and Venous phase (CT40 keV, CT50 keV, CT60 keV, CT70 keV), iodine concentration (IC) and effective atomic number (Zeff) were measured, then the normalized IC(NIC) and spectral curve(K(40-70)) value were calculated. The differences of each parameter derived from spectral CT between the two groups were compared, and a logistic regression model was constructed. The ROC curves and area under the curve (AUC) were conducted to evaluate the diagnostic performance of each parameter and Delong test was used to compare the difference of each AUC. Results: Compared to nonmetastatic LNs group, metastatic LNs group had higher maximum diameter of tumor, CT40 keV, CT50 keV, CT60 keV, CT70 keV, IC, NIC, Zeff, and K(40-70) values on venous phase (the representative parameter is Zeff: 8.4 (8.2, 8.5) vs 8.2 (8.1, 8.3)) (all P<0.05). The proportion of patients with lower histology differentiated degree, higher T grade and positive carcino embryonic antigen (CEA)were higher than that in nonmetastatic LNs (the representative parameter was CEA: 34.6%(36/104) vs 7.7%(2/26) (all P<0.05). The regression model constructed by CEA and Zeff had the highest predictive value in predicting metastatic LNs, with an AUC of 0.835(0.759-0.894), sensitivity and specificity of 83.65% and 73.08%, respectively. Conclusion: SDCT quantitative parameters on venous phase and CEA facilitate the accurate prediction of metastatic LNs in patients with gastric cancer, and the multi-parameter regression model has the highest diagnostic performance.

A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients.

Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS "CD8+ TOXPHOS cells." We validated that higher levels of OXPHOS in tumor- and peripheral blood-derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients.

[Renal sympathetic denervation can significantly reduce blood pressure and improve arterial stiffness in hypertensive beagles].

OBJECTIVE: To investigate the effect of renal sympathetic denervation (RDN) on blood pressure and arterial stiffness in hypertensive beagles and explore the underlying mechanism. METHODS: Sixteen beagles were randomly divided into RDN group (n=8, fed with a high-salt high-fat diet to establish models of hypertension and treated with RDN), sham-operated group (n=4, fed with a high-salt high-fat diet to induce hypertension but only examined with renal arteriography) and control group (n=4, fed with formula dog food). The changes in blood pressure, arterial stiffness, endothelial function, and sympathetic activity were compared among the 3 groups and correlation analysis was performed. RESULTS: All the animal models of hypertension were established successfully in the beagles. At 3 months after the RDN, the changes in systolic blood pressure (SBP) differed significantly among the 3 groups (P=0.006), and the reduction in SBP was significantly greater in RDN group than in the other two groups (P < 0.05). The variations of diastolic blood pressure (DBP) also differed significantly among the 3 groups (P=0.016), and DBP reduction was more obvious in RDN group than in the control group (P=0.007), but similar to that in the sham-operated group (P=0.052). The changes of resistance index (RI) after the procedure were significantly different among the 3 groups (P=0.043), and the RDN group showed a greater reduction of RI than the control group (P=0.032) and sham group (P=0.043). Serum levels of eNOS, NO and Ang Ⅱ did not differ significantly among the groups either before or after RDN (P>0.05), but serum NE level was significantly higher in RDN group than in the control groupafter successful modeling (P=0.014), but similar to that in the sham group (P=0.560). Compared with the sham operation, RDN in the hypertensive beagles resulted in a significantly greater decrease of serum NE level (P=0.032) to almost the control level (P= 0.080). The changes of RI following RDN were significantly correlated with the changes of SBP, DBP and serum levels of NO and NE (P < 0.05). CONCLUSION: RDN can significantly reduce blood pressure and improve arterial stiffness in hypertensive beagles possibly by reducing sympathetic activity and blood pressure and promoting NO synthesis.

[Efficacy and safety of percutaneous closure of ventricular septal rupture after acute myocardial infarction: a clinical study of 69 cases].

Objective: To investigate the efficacy and safety of percutaneous closure of ventricular septal rupture (VSR) after acute myocardial infarction (AMI) and the risk factors of all-cause mortality at 30 days after operation. Methods: This is a retrospective case series study. A total of 69 patients with post-AMI VSR, underwent percutaneous closure of VSR from October 2013 to May 2020 in Department of Cardiology of Henan Provincial People's Hospital and Department of Cardiology of Central China Fuwai Hospital, were included. Patients were divided into survival group (53 cases) and non-survival group (16 cases) according to the status at 30 days after operation. Clinical data were collected and analyzed during hospitalization. Telephone follow-up was performed 30 days after operation. The primary safety endpoint was occlusion failure and all-cause mortality at 30 days post operation. The secondary safety endpoint was the operation related or non-operation related complications. Efficacy endpoint included NYHA classification of cardiac function, index measured by right heart catheterization and echocardiography. Multivariate logistic regression was performed to analyze the risk factors of all-cause mortality at 30 days after operation. Results: A total of 69 patients, aged 67 (64, 71) years, including 42 women (60.9%), were enrolled in this study. All-cause death occurred in 16 patients (23.2%), including 13 in-hospital death and 3 death during follow-up. There were 4 cases of closure failure (5.8%). Among the 65 patients with successful closure, 12 (18.5%) experienced operation-related complications, among which 8 (12.3%) experienced valve injury. The mortality was significantly higher in patients with operation-related complications than that in patients without operation-related complications (41.7% (5/12) vs. 13.2% (7/53), P = 0.022). One case received percutaneous closure of VSR and PCI, this patient experienced new-onset AMI immediately post procedure and died thereafter (1.5%). One case (1.5%) developed multiple organ failure and 2 cases (3.1%) developed gastrointestinal bleeding post operation. All of the 65 patients with successful occlusion completed postoperative echocardiography, 56 patients completed cardiac function assessment at discharge, and 53 patients who survived up to 30 days post discharge completed clinical follow up by telephone. The NYHA cardiac function at discharge and 30 days after operation were significantly improved as compared to that before operation (P<0.001), the ratio of NYHA Ⅰ and Ⅱ patients was significantly higher post operation at these two time points as compared to baseline level (76.8% (43/56) vs. 23.1% (15/65), P<0.001, 77.4% (41/53) vs. 23.1% (15/65), P<0.001). The pulmonary circulation/systemic circulation blood flow ratio (Qp/Qs), pulmonary artery systolic pressure (PASP) and left ventricular end-diastolic diameter (LVDd) were decreased, aortic systolic pressure (ASP) and left ventricular ejection fraction (LVEF) were increased post operation (P<0.05). Multivariate logistic regression analysis showed that WBC>9.8×109/L (OR=20.94, 95%CI 1.21-362.93, P=0.037) and NT-ProBNP>6 000 ng/L (OR=869.11, 95%CI 2.93-258 058.34, P=0.020) were the independent risk factors of mortality at 30 days. Conclusions: Percutaneous closure in VSR after AMI is safe and effective. The increase of WBC and NT-ProBNP are the independent risk factors of all-cause mortality at 30 days after operation.

Mechanisms of primary and acquired resistance to PD-1/PD-L1 blockade and the emerging role of gut microbiome

As a very promising immunotherapy, PD-1/PD-L1 blockade has revolutionized the treatment of a variety of tumor types, resulting in significant clinical efficacy and lasting responses. However, these therapies do not work for a large proportion of patients initially, which is called primary resistance. And more frustrating is that most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms that lead to primary and acquired resistance to PD-1/PD-L1 inhibition have remained largely unclear. Recently, the gut microbiome has emerged as a potential regulator for PD-1/PD-L1 blockade. This review elaborates on the current understanding of the mechanisms in terms of PD-1 related signaling pathways and necessary factors. Moreover, this review discusses new strategies to increase the efficacy of immunotherapy from the perspectives of immune markers and gut microbiome (AU)

[Efficacy of combined treatment with mechanical circulation support devices and immunomodulation therapy for patients with fulminant myocarditis].

Objective: To summarize the efficacy of combined treatment strategy of mechanical circulation support devices and immunomodulation therapy for patients with fulminant myocarditis. Method: We retrospectively analyzed the clinical data and outcomes of 37 fulminant myocarditis patients complicating cardiogenic shock, who were hospitalized from October 2017 to December 2019 in our department. Patients received guideline therapy according to "Chinese expert consensus statement on clinical diagnosis and treatment of fulminant myocarditis in adults"issued by Chinese Society of Cardiology of Chinese Medical Association. Patients were divided into IABP group (n=19), ECMO group (n=5) and IABP+ECMO group (n=13) according to different mechanical circulation support regimen. The treatment effectiveness among various groups were compared. The major endpoint was in-hospital mortality. The duration and outcome of mechanical circulation support were also analyzed. Furthermore, relationships between baseline data, proportion of different treatments (including medicine treatment, temporary pacemaker and continuous renal replacement treatment, immunomodulation therapy) and clinical outcome were analyzed. Results: The age of the 37 patients in the cohort was (37.4±17.0) years, and there were 22 male among them. Immunomodulation therapy included glucocorticoid (methylprednisolone) and intravenous immunoglobin. At admission, blood pressure was (70.21±17.37)mmHg(1 mmHg=0.133 kPa),heart rate was(100±30)beat/minutes,there were 10 cases of Ⅲ° atrioventricular block and all received temporary pacemaker implantation, 12 cases of ventricular tachycardia and fibrillation,1 patient received temporary pacemaker implantation due to electronic storm, peak cardiac troponin I level was (18.61±9.55)µg/L, peak B type natriuretic peptide level was 1 670(518,3 410)ng/L,left ventricular ejection fraction (LVEF) was(32.3±10.4)%. Thirty-four out of the 37 patients survived and 3 patients died. Hospital duration was (22.7±8.2)days, LVEF was (50.1±10.5)% at discharge. Lactic acid level was significantly higher in IABP+ECMO group than in IABP group and ECMO group(P<0.001 or =0.005),LVEF was significantly lower in IABP+ECMO group than in IABP group(P=0.004),the proportion of ventilator usage was higher in IABO+ECMO group than in IABP group (P<0.05). Survival rate was similar among the three groups. Conclusion: Comprehensive treatment regimen with combined mechanical circulation support and immunomodulation therapy as the core strategies is effective in the treatment of fulminant myocarditis complicated with cardiogenic shock.

[Prognostic values of spindle checkpoint protein BUB1B in triple negative breast cancer].

Objective: To identify important prognostic molecular markers of triple negative breast cancer (TNBC) using high throughput sequencing technology and to explore the correlation of spindle checkpoint protein BUB1B and clinicopathological features with patients' prognosis. Methods: The clinicopathological data and prognostic information of TNBC diagnosed at the West China Hospital of Sichuan University from 2009 to 2017 were collected. Forty-seven fresh tumor samples and 139 formalin fixed paraffin-embedded samples were selected. The fresh tumor samples were subject to RNA sequencing (RNA-seq). The enrichment analysis and protein-protein interaction (PPI) analysis were performed after intersection of difference analysis between RNAseq and GEO (Gene Expression Omnibus) datasets GSE38959 and GSE65194. Kaplan-Meier plotter database was used to analyze the relationship between expression of BUB1B and prognosis. Immunohistochemical staining was used to verify its expression in TNBC and correlation with clinicopathological features and prognosis. Results: Using edgeR to perform differential expression analysis between 47 TNBC tumor tissues and 12 normal tissues, 1 559 up-regulated genes and 1 376 down-regulated genes were identified, while only 131 differentially expressed genes were overlapping with those in GSE38959 and GSE65194. Enrichment analysis was mainly enriched in cell cycle, JAK-STAT signaling pathway and p53 signaling pathway. The top 10 genes ranked by degree of association were TOP2A, BUB1B, MKI67, PLK1, RRM2, PCNA, KPNA2, SMC4, PBK and IGF1. Kaplan-Meier plotter database analysis showed that the expression of BUB1B was significantly correlated with the prognosis of TNBC [overall survival, hazard ratio (HR)=0.52, 95%CI (0.35-0.77), P=0.001; distant metastasis-free, HR=0.72, 95%CI (0.52-0.98), P=0.038]. The immunohistochemical analyses of 139 formalin fixed paraffin-embedded samples showed that the low expression of BUB1B was correlated with poor prognosis in TNBC [HR=0.41, 95%CI (0.18-0.95), P=0.024]. Conclusions: The low expression of BUB1B protein is associated with poor prognosis in TNBC patients, and the molecular mechanism related with prognosis and potential therapeutic targets need to be further studied.

Mechanisms of primary and acquired resistance to PD-1/PD-L1 blockade and the emerging role of gut microbiome.

As a very promising immunotherapy, PD-1/PD-L1 blockade has revolutionized the treatment of a variety of tumor types, resulting in significant clinical efficacy and lasting responses. However, these therapies do not work for a large proportion of patients initially, which is called primary resistance. And more frustrating is that most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms that lead to primary and acquired resistance to PD-1/PD-L1 inhibition have remained largely unclear. Recently, the gut microbiome has emerged as a potential regulator for PD-1/PD-L1 blockade. This review elaborates on the current understanding of the mechanisms in terms of PD-1 related signaling pathways and necessary factors. Moreover, this review discusses new strategies to increase the efficacy of immunotherapy from the perspectives of immune markers and gut microbiome.

Circular RNA circ-NT5C2 acts as a potential novel biomarker for prognosis of osteosarcoma.

We detected some serious inaccuracies and mistakes. Therefore, the article, "Circular RNA circ-NT5C2 acts as a potential novel biomarker for prognosis of osteosarcoma, by W.-B. Nie, L.-M. Zhao, R. Guo, M.-X. Wang, F.-G. Ye, published in Eur Rev Med Pharmacol Sci 2018; 22 (19): 6239-6244-DOI: 10.26355/eurrev_201810_16030-PMID: 30338784" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/16030.

Retraction notice to "30MO ORIENT-3: A randomized, open-label, phase III study of sintilimab versus docetaxel in previously treated advanced/metastatic squamous non-small cell lung cancer (sqNSCLC)": [Annals of Oncology Volume 31, Supplement 7, December 2020, Page S1428].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article was retracted at the request of the authors. The authors of this abstract have advised that full agreement between authors and sponsors on publication of the abstract has not been reached and they are therefore unable to publish this data at present.

[Value of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging and diffusion-weighted MR imaging in predicting microvascular invasion in hepatocellular carcinoma and the prognostic significance].

Objective: To investigate the combined value of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) in predicting pathological microvascular invasion (pMVI) preoperatively, and to determine the relationship between prediction results and prognosis in hepatocellular carcinoma (HCC) patients. Methods: A total of 181 newly diagnosed HCC patients were enrolled in this study. Imaging characteristics and the apparent diffusion coefficient (ADC) value of DWI were analyzed. The differences of imaging characteristics and ADC values between different pMVI groups were analyzed.Multivariate logistic regression and receiver operating characteristic (ROC) curve were used to analyze the value for pMVI prediction by using significant parameters. The patients were grouped based on MRI predicted MVI (mrMVI), and the relationship between mrMVI and recurrence free survival time (RFS) was analyzed. Results: Fifty-one patients were pMVI positive and 130 patients were pMVI negative. The ADC value in pMVI positive group were (1.10±0.17)×10(-3) mm(2)/s, significantly lower than (1.27±0.22)×10(-3) mm(2)/s of pEMVI negative group (P<0.001). The incidence rates of incomplete enhancing "capsule" , non-smooth tumor margin, arterial peritumoral enhancement, mosaic architecture and peritumoral hypointensity on hepatobiliary phase (HBP) in pMVI positive group were significantly higher than those of negative group (all P<0.05). Multivariate logistic regression analysis showed that tumor margin, arterial peritumoral enhancement, peritumoral hypointensity on HBP and ADC value were independently associated with pMVI. ROC analysis showed that the area under curve, sensitivity and specificity of pMVI predicted by combined parameters were 0.830, 76.5% and 81.5%, respectively. The median RFS of mrMVI positive group was 23.6 months, significantly lower than 38.2 months of mrEMVI negative group (P=0.004). Conclusion: Tumor margin, arterial peritumoral enhancement, peritumoral hypointensity on HBP and ADC value are independent predictors of pMVI in HCC, and mrMVI is related with RFS.

Comparison of overfeeding effects on gut physiology and microbiota in two goose breeds.

To have a better understanding of how the "gut-liver axis" mediates the lipid deposition in the liver, a comparison of overfeeding influence on intestine physiology and microbiota between Gang Goose and Tianfu Meat Goose was performed in this study. After force-feeding, compared with Gang Goose, Tianfu Meat Goose had better fat storage capacity in liver (397.94 vs. 166.54 for foie gras weight (g), P < 0.05; 6.37 vs. 2.92% for the ratio of liver to body, P < 0.05; 60.01 vs. 46.64% for fat content, P < 0.05) and the less subcutaneous adipose tissue weight (1240.96 g vs. 1440.46 g, P < 0.05). After force-feeding, the digestion-absorption capacity of Tianfu Meat Goose was higher than that of Gang Goose (5.56 vs. 3.64 and 4.63 vs. 3.68 for the ratio of villus height to crypt depth in duodenum and ileum, respectively, P < 0.05; 1394.96 vs. 782.59 and 1314.76 vs. 766.17 for the invertase activity (U/mg-prot), in duodenum and ileum, respectively, P < 0.05; 6038.36 vs. 3088.29 and 4645.29 vs. 3927.61 for the activity of maltase (U/mg-prot), in duodenum and ileum, respectively, P < 0.05). Force-feeding decreased the gene expression of Escherichia coli in the ileum of Tianfu Meat Goose; force-feeding increased the number of gut microbiota Enterobacterial Repetitive Intergenic Consensus-Polymerase Chain Reaction band in Tianfu Meat Goose and decreased the number in Gang Goose. In conclusion, compared with Gang Goose, the lipid deposition in the liver and the intestine digestion-absorption capacity and stability were higher in Tianfu Meat Goose. Thereby, Tianfu Meat Goose is the better breed for foie gras production for prolonged force-feeding; Gang Goose possesses better fat storage capacity in subcutaneous adipose tissue. However, Gang Goose has lower gut stability responding to force-feeding, so Gang Goose is suited to force-feeding in a short time to gain the body weight and subcutaneous fat as an overfed duck for roast duck.

Magnetic crystalline-symmetry-protected axion electrodynamics and field-tunable unpinned Dirac cones in EuIn2As2.

Knowledge of magnetic symmetry is vital for exploiting nontrivial surface states of magnetic topological materials. EuIn2As2 is an excellent example, as it is predicted to have collinear antiferromagnetic order where the magnetic moment direction determines either a topological-crystalline-insulator phase supporting axion electrodynamics or a higher-order-topological-insulator phase with chiral hinge states. Here, we use neutron diffraction, symmetry analysis, and density functional theory results to demonstrate that EuIn2As2 actually exhibits low-symmetry helical antiferromagnetic order which makes it a stoichiometric magnetic topological-crystalline axion insulator protected by the combination of a 180∘ rotation and time-reversal symmetries: [Formula: see text]. Surfaces protected by [Formula: see text] are expected to have an exotic gapless Dirac cone which is unpinned to specific crystal momenta. All other surfaces have gapped Dirac cones and exhibit half-integer quantum anomalous Hall conductivity. We predict that the direction of a modest applied magnetic field of µ0H ≈ 1 to 2 T can tune between gapless and gapped surface states.

[A prospective multi-center clinical investigation of HIV-negative pulmonary cryptococcosis in China].

Objective: To investigate the current status of the diagnosis and treatment of pulmonary cryptococcosis in respiratory medicine and improve the understanding of the clinical characteristics of HIV-negative pulmonary cryptococcosis in China. Methods: A prospective multi-center open cohort study was designed to screen for pulmonary cryptococcosis in the general wards and intensive care units of the Department of Respiratory Diseases in 22 hospitals. The HIV-negative patients with positive cryptococcal etiological diagnosis based on smear culture, antigen detection and histopathology were enrolled in the study. The clinical data of enrolled patients were collected and analyzed. Results: A total of 457 cases of pulmonary cryptococcosis were enrolled, among which 3.28% (15/457) were disseminated infections. The case fatality rate was 0.88% (4/457). The majority of the cases were diagnosed by histopathological examinations (74.40%, 340/457) and cryptococcus antigen detection (37.64%, 172/457). Patients with pulmonary cryptococcosis accounted for 2.04‰ (457/223 748) of the total hospitalized patients in the Department of Respiratory Diseases during the same period, and the ratio was the highest in south and east China. Meanwhile, 70.24% (321/457) of the patients had no underlying diseases, while 87.75% (401/457) were found to have immunocompetent status. Cough and expectoration were the most common clinical symptoms in patients with pulmonary cryptococcosis. However, 25.16% (115/457) of the patients had no clinical symptom or physical signs. In terms of imaging features on pulmonary CT, multiple pulmonary lesions were more common than isolated lesions, and there were more subpleural lesions than perihilar or medial lesions. Morphologically, most of the lesions were middle-sized nodules (1-5 cm) or small-sized nodules (3 mm to 1 cm). The sensitivity of serum cryptococcus antigen test was 71.99% (203/282). Moreover, antigen-positive patients differed from antigen-negative patients in terms of basic immune status, clinical symptoms, imaging features and infection types. Meanwhile, immunocompromised patients differed from immunocompetent patients in terms of clinical symptoms, physical signs, infection-related inflammation indicator levels, imaging features, serum cryptococcus antigen positive rate and prognosis. Conclusions: The majority of cases of HIV-negative pulmonary cryptococcosis in China had no underlying disease or immunocompromised status, and the overrall prognosis was favorable. However, early diagnosis of HIV-negative pulmonary cryptococcosis remains challenging due to the complicated manifestations of the disease.

Luteoloside Ameliorates Palmitic Acid-Induced in Vitro Model of Non-alcoholic Fatty Liver Disease via Activating STAT3-Triggered Hepatocyte Regeneration.

Luteoloside (Lute), a bioactive natural ingredient, widely exists in nature and possesses hepatoprotective and hepatocyte proliferation-promoting properties. This study aimed to investigate whether Lute could counteract non-alcoholic fatty liver disease (NAFLD)-caused hepatocyte damage via its stimulation of hepatocyte regeneration efficacy and to explore the involved mechanism. LO2 cells and primary hepatocytes were used to examine the hepatocyte proliferation effects of Lute under physiological conditions and in the palmitic acid (PA)- induced in vitro model of NAFLD. STAT3 and cell cycle-related proteins (cyclin D1, c-myc and p21) were evaluated by Western blot. Under physiological conditions, LO2 cells and primary hepatocytes treated with various concentration of Lute for 12 and 24 h showed increased hepatocyte proliferation, especially with 20 µM treatment for 24 h. More notably, under the model conditions, co-incubation with 20 µM of Lute also markedly reversed PA-induced inhibition of cell proliferation and viability in primary hepatocytes. Mechanistically, Lute could activate STAT3 and subsequently increase cyclin D1 and cmyc expression, which positively regulates cell cycle progression, and decrease expression of p21, an inhibitor of cell cycle progression. Furthermore, Luteinduced hepatocyte proliferation-promoting efficacy was abolished by STAT3 inhibitor stattic. Collectively, Lute can alleviate PA-induced hepatocyte damage via activating STAT3-mediated hepatocyte regeneration.

Research progress into the physiological changes in metabolic pathways in waterfowl with hepatic steatosis.

1. When geese or ducks are overfed with a high-energy diet rich in carbohydrates, their liver increases in size by 5- to 10-fold in 2 weeks, which is accompanied by the occurrence of hepatic steatosis. As a result, this distinctive genetic characteristic of waterfowl has been taken advantage of to produce foie gras. 2. When overfed geese were fed a regular diet for a 20-d period of recovery, their liver was restored to the original state. Hence, the entire process is reversible, and cause no lasting cirrhosis or necrosis in the liver. This suggests that waterfowl have a mechanism to protect their liver from the harm caused by severe hepatic steatosis. 3. This paper reviews the formation, physiological changes to metabolic pathways and the protective mechanisms in geese and ducks with hepatic steatosis. Not only will understanding these mechanisms provide ideas for the waterfowl breeding selection for foie gras, it is conducive to improving production efficiency and quality of foie gras. This provides a scientific basis to ensure animal welfare and an approach to the prevention and treatment of fatty liver disease in human.